14-92071010-C-CCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_004993.6(ATXN3):c.915_916insCAGCAGCAGCAG(p.Gln302_Gln305dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 20)
  • Exomes 𝑓: 0.0053 (165 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATXN3 NM_004993.6 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.168

Genes affected

ATXN3 (HGNC:7106): (ataxin 3) Machado-Joseph disease, also known as spinocerebellar ataxia-3, is an autosomal dominant neurologic disorder. The protein encoded by this gene contains (CAG)n repeats in the coding region, and the expansion of these repeats from the normal 12-44 to 52-86 is one cause of Machado-Joseph disease. There is a negative correlation between the age of onset and CAG repeat numbers. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 14-92071010-C-CCTGCTGCTGCTG is Benign according to our data. Variant chr14-92071010-C-CCTGCTGCTGCTG is described in ClinVar as [Benign]. Clinvar id is 931861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00866 (1234/142494) while in subpopulation AFR AF= 0.0202 (734/36306). AF 95% confidence interval is 0.019. There are 24 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd at 1227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATXN3	NM_004993.6	c.915_916insCAGCAGCAGCAG	p.Gln302_Gln305dup	inframe_insertion	10/11	ENST00000644486.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATXN3	ENST00000644486.2	c.915_916insCAGCAGCAGCAG	p.Gln302_Gln305dup	inframe_insertion	10/11		NM_004993.6	P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1227 AN: 142384 Hom.: 24 Cov.: 20

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.00847

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00928

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00534 AC: 7015 AN: 1314362 Hom.: 165 Cov.: 92 AF XY: 0.00515 AC XY: 3384 AN XY: 657202

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.00548

Gnomad4 ASJ exome AF: 0.000123

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00592

GnomAD4 genome AF: 0.00866 AC: 1234 AN: 142494 Hom.: 24 Cov.: 20 AF XY: 0.00861 AC XY: 596 AN XY: 69228

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00847

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.00917

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Azorean disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 16, 2018

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: A. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922928; hg19: chr14-92537354;